Exjade™ (deferasirox) is a marketed product from Novartis that is formulated as dispersible tablets in 125 mg, 250 mg and 500 mg dose strengths. Exjade™ (deferasirox) is given once daily for the treatment of chronic iron overload due to blood transfusions, which is referred to by medical professionals and clinicians as transfusional hemosiderosis, in patients 2 years of age and older.
Due to the poor solubility of Exjade™ (deferasirox), a high dose is required to achieve the desired therapeutic effect, which results in unwanted side effects, such as gastrointestinal (GI) irritation and kidney toxicity. The poor solubility of Exjade™ (deferasirox) also presents technical difficulties in developing pharmaceutical formulations, as seen from the solubility profile summarized in Table 1. To meet the high dose requirement and reduce pill burden Exjade™ (deferasirox) was developed as dispersible tablets with about 29.4% drug load. The disadvantage of this type of formulation is that the tablets have to be dispersed in water or appropriate liquid, such as in orange juice or apple juice and stirred until a fine suspension is obtained prior to administration. Further, the dispersible tablets have to be taken at least 30 minutes before food.
TABLE 1Exjade ™ (deferasirox) Solubility ProfilepHSolubility (mg/ml) at 37 C.water0.021<0.012<0.013<0.014<0.015<0.017.50.167
Gastrointestinal (GI) irritation has been reported for patients using the current dispersible tablets. Upper gastrointestinal ulceration and hemorrhage has also been reported in patients, including children and adolescents. Multiple ulcers have been observed in some patients. Stomach bleeding is a severe side effect that occurs for patients currently under Exjade therapy because of acidity of Exjade™ (deferasirox), and local accumulation of drug content. Therefore, it is desirable to re-formulate an Exjade™ (deferasirox) dispersible formulation to limit the direct contact of drug compound with stomach mucosa. It is further desirable to provide a high load deferasirox formulation that has no food effect. For instance, as enteric coated form or multi-particulate form where dosage form is emptied faster from the stomach. In addition, data from THALASSA (NTDT) study placebo arms (contains all components in Exjade™ dispersible tablets (except API) suggest that excipients in the marketed dispersible formulation could contribute to GI adverse effects (AE) profile of Exjade™.
The current invention describes formulated compositions and the corresponding technology of manufacturing tablets for Exjade™ (deferasirox) to prevent gastrointestinal irritation, having no food effect and improve patient compliance.
With aforementioned cumbersome in drug administration, it is also desirable to re-formulate the current dispersible Exjade™ (deferasirox) tablets into swallowable (ingestable, orally administerable) tablets and sachets, which increase the drug load by up to and greater than 100% of the current dispersible tablet and sachet per dose requiring less pill burden while maintaining equivalent pharmacokinetic profile, and consequently the therapeutic outcome as compared to commercially marketed dispersible Exjade™ (deferasirox) tablets.